PROJECT SUMMARY/ABSTRACT Alzheimer's disease is a chronic neurodegenerative disease that causes progressive cognitive decline and has thus far proven incurable. With an aging population, this devastating disease will become more widespread in the near future, making the search for effective treatments a principle objective. Brain pathology is marked by amyloid plaques and neurofibrillary tangles, but it is unknown if these are causative, and numerous treatment strategies targeting amyloid have proven unsuccessful thus far. Cerebrovascular signaling has been shown to play an important role in aging and in neurodegenerative diseases including Alzheimer's. In particular, cerebrovascular TGF-? signaling undergoes a marked decline in these conditions, potentially exacerbating disease symptoms. Indeed, mice lacking TGF-? signaling specifically in endothelial cells have increased blood- brain barrier permeability and hemorrhage. Restoring deficient TGF-? signaling is beneficial and promotes amyloid clearance in mouse models of Alzheimer's disease while inhibiting signaling exacerbates pathology, but the mechanism and cell types responsible remain unclear. Brain endothelial cells are responsible for neurovascular homeostasis and mediating the response to vascular signals, and have been shown to be dysfunctional in Alzheimer's disease. This current study will characterize changes in brain endothelial cell TGF- ? signaling during aging and in mouse models of Alzheimer's disease, and determine the effects of these changes on blood-brain barrier permeability. Specifically, using genetic models to regulate TGF-? signaling in brain endothelial cells in mice, an orally bioavailable small molecule activator of TGF-? signaling in the brain, and novel bioorthogonal chemistry and imaging tools to assess blood-brain barrier function, this study aims to determine whether the loss of TGF-? signaling during aging and Alzheimer's disease impairs endothelial and neurovascular function, contributing to disease pathology, and whether reversing this loss in signaling has therapeutic potential. Ultimately, these studies pursue the innovative concept that cerebrovascular TGF-? signals play an important and overlooked role in Alzheimer's disease, and that restoring these signals can be exploited therapeutically.